Sexual dysfunction is the result of different mechanisms in males and females. In males impotence is defined as the inability to obtain an erection sufficient for intercourse. Erection is achieved as a result of blood inflow into the corpora cavernosa of the penis, which produces engorgement of the corpora cavernosa, and subsequent penile erection. It is estimated that as many as 30 million American men experience some degree of erectile dysfunction, the prevalence of which increases with age (Feldman et al., J. Urol. 151: 54-61, 1994).
The causes of impotence can be divided into two subcategories: 1) organic and 2) psychological. The organic aspects of impotence are caused by underlying vascular disease such as that associated with hypertension, diabetes mellitus and prescription medications. About half of all cases of impotence are of vascular origin. Because the physiologic process of erection is initiated by an increase in blood flow through the penile arteries and shunting of blood into the vascular spaces of the corpora cavernosa, erectile dysfunction can result from the inability of the arteries of the penis to dilate, thereby inhibiting the flow of blood into the erectile tissue.
The sympathetic pathways play a primary role in the neural control of penile erection. It is generally accepted that, in the detumescent state, release of noradrenaline (NA), acting on postjunctional α1-receptors on the cavernous arteries and on the corpora cavernosa (Christ et al., Br. J. Pharmacol. 101: 375-381, 1990), contributes to keep the penile smooth muscle contracted. Conversely, intracavernous injection of a1-antagonists like phenoxybenzamine, phentolamine and moxisylyte produced tumescence and erection (see for review Andersson K. -E, Pharmacol. Rev. 45: 253-308, 1993; Montorsi et al., Drugs 50: 465-479, 1995; Hatzichristou D. G., Int. J. Impot. Res. 10: S3-S13, 1998).
The erectile response to transurethral prazosin in human males has been recently reported (Peterson et al., J. Urol. 159: 1527-1528, 1998) as well as the relaxing effect of this antagonist on human male, dog and rat isolated penile tissues and vessels (Hedlund and Andersson, J Auton. Pharmacol. 5: 81-88, 1985; Holmquist et al., Eur. J. Pharmacol 186: 87-93, 1990; Hayashida et al., Jpn. J. Pharmacol. 72: 231-240, 1996).
In females the sexual response initiates with a stimulation which causes vasocongestion and results in lubrication of the vagina in preparation for penis insertion. Lubrication is due to formation of an exudate which, together with genital congestion, produces the so-called orgasmic platform which preludes to orgasm. In brief, female sexual dysfunction may be due to interference with the different stages of intercourse and can be related to either organic or functional causes, or both.
Several reasons including stress, anxiety, depression, fatigue, interpersonal conflicts between the partners or more simply ageing, can lead to failure of the vasocongestive response, thereby inhibiting normal vaginal lubrication. Women in this condition may be incapable of achieving a normal sexual response without appropriate treatments (Harrisons' Principles of Internal Medicine, 14th Ed., page 291, McGraw-Hill (1998)). It has been recently confirmed that both vaginal vasocongestion and clitoral erection depend on increased blood flow (Park K. et al., Int. J. Impot. Res. 9, 27-37 (1997)).
Moreover, similarly to what reported for the male sexual organ, the same authors demonstrated that a local injection in the vagina of α1-adrenergic antagonists such as phentolamine can increase blood flow and intravaginal pressure up to levels comparable with those achieved by stimulation of the pelvic nerve. These data clearly indicate that noradrenaline plays an important role in maintaining flaccidity of the organ concerned in the female sexual tract too.
It is thus important to identify new products having an α1-adrenoceptor antagonistic activity, which can be useful in promoting vasodilatation of the arteries in the vaginal walls and clitoris, thereby improving lubrication and helping continuation of the sexual act.
Pharmacological, biochemical and radioligand binding studies evidenced three different α1-receptor subtypes with a high affinity for prazosin, namely α1A-(α1a-), α1B-(α1b-) and α1D-(α1d-), with lower case subscripts being used for recombinant receptors and upper case subscripts for receptors in native tissues (Hieble et al., Pharmacol. Rev. 47: 267-270, 1995). In functional studies α1-receptors with a low affinity for prazosin have also been identified and termed α1L-receptors (Flavahan et al., Trends Pharmacol. Sci. 7: 347-349, 1986; Muramatsu et al., Pharmacol. Comm. 6: 23-28, 1995).
Several studies have demonstrated the presence of these α1-adrenergic receptor subtypes in the animal and human cavernous tissues. By using in situ hybridization with specific oligonucleotide probes and protection assays techniques (Traish, A., et al., J. Urol. 153: 222-227, 1995; Traish, A., et al., Receptor 5: 145-157, 1995; Vèronneau-Longueville et al., Int. J. Impot. Res. 10: 187-194, 1998) demonstrated that human and rat corpus cavernosum tissues expressed all three cloned α1-adrenergic receptor subtypes.
On the other hand, functional studies in male human penile tissue are controversial, suggesting the involvement of all three cloned α1-ADR subtypes (Traish et al. J. Urol. 153: 222-227, 1995), or that the α1L-ADR subtype is the main mediator of NA-induced contraction in this tissue (Davids et al. Br. J. Pharmacol. 125: 13P, 1998). Conversely, nothing is known so far about vaginal vessels.
Pharmacological evidence for the univocal presence of a well defined α1-adrenergic receptor subtype(s) in the penile or vaginal tissue would represent a major advance in the field of male and female sexual dysfunction treatment, allowing the possibility of the use of selective α1-antagonists.
The α-antagonists currently being used for the treatment of predominantly male impotence suffer from unwanted side effects, such as priapism, a painful erection of exceeding long duration which may result in fibrosis of cavernous tissue (Brindley et al., Br. J. Pharmacol 87, 495-500, 1986). Other side effects are penile pain and hypotension (Peterson et al. J. Urol. 159: 1523-1527, 1998).
Thus there is still a need for selective α1-antagonists which do not subject the impotent patient to the side effects of known treatments, notably of the cardiovascular type.
Accordingly, it is a primary object of the present invention to provide a method of treating impotence, both male and female, which avoids any excessive side effects due to acute hypotension.
It is another object of the present invention to provide pharmaceutical compositions comprising selective α1b-adrenoceptor antagonists, which compositions are effective for the treatment of male erectile impotence and female sexual dysfunction.
It is another object of the present invention to provide a method of treating sexual dysfunction using selective α1b-adrenoceptor antagonists.
Other features and advantages of the present invention will be apparent to those of skill in the art from the following detailed description and appended claims.